Marijuana: A Possible Treatment for Depression?

Recently there has been debate over whether the popular recreational drug marijuana (see image at left) has legitimate medical uses. Several states, including California, have decriminalized marijuana usage for patients who have been told by their doctors that they could benefit from the drug. The main, if controversial, recognized medical use of marijuana has to do with its supposed pain-relieving effect. It is often recommended to cancer and AIDS patients to alleviate the chronic pain that often accompanies those diseases. According to the National Organization for Reforming Marijuana Laws (NORML), an organization that promotes the legalization of marijuana, it has also been recognized for “symptomatic relief for a number of medical conditions, including nausea and vomiting, stimulating appetite, promoting weight gain, and diminishing intraocular pressure from glaucoma.” However, the Drug Enforcement Agency of the United States classifies marijuana as a Schedule I drug, meaning it, among other things, “has no currently accepted medical use in treatment in the United States.” Nevertheless, a new study (the full text article requires a subscription) published in the current issue of The Journal of Neuroscience may add antidepressant to marijuana’s list of medical uses.

The new research studied the effect of tetrahydrocannabinol (THC), the active chemical in marijuana, on rats. Among other experiments, the researchers used a “Forced Swim Test” or FST to evaluate the drug’s antidepressant properties. This test involves placing the rats in water too deep to stand in and seeing how long it takes until they give up trying to swim. The basic idea is that more “depressed” rats will give up on surviving sooner. In the words of the study, “The FST is both sensitive and selective for clinically effective antidepressants, has been repeatedly validated, and is currently the most popular model for detecting antidepressant activity attributable to its simplicity, reliability, and high predictive validity.” The researchers also directly measured serotonin activity in the rats’ brains. The results showed that low doses of THC produced similar effects to SSRI (selective serotonin reuptake inhibitor) antidepressants, meaning they increased the rats’ swimming behavior in the FST (see graph below right where WIN is the THC and DIM is the SSRI used for comparison) and increased serotonin activity in their brains. On the other hand, high doses of THC did not affect the results of the FST and actually lowered serotonin activity. THC exerts its effect by activating the brain’s endocannabinoid system, which can be thought of as the brain’s stress-recovery mechanism.

I should note that this study does not necessarily translate to typical recreational marijuana use in humans. First, even though rats are often used as models for human diseases, the human brain is still infinitely more complex than the rat brain and therefore THC may influence it differently. Also, recreational marijuana is usually smoked, and this makes it difficult to control the amount of THC entering the bloodstream. As stated above, high doses of THC have detrimental effects on the brain systems thought to be responsible for mood, and therefore the researchers cautioned against attempting to use smoked marijuana as an antidepressant. In addition, marijuana and particularly smoked marijuana have other negative effects including “frequent respiratory infections, impaired memory and learning, increased heart rate, anxiety, panic attacks and tolerance,” as indicated by the White House’s fact sheet on the drug. Marijuana has also been shown in some studies to be addictive and cause physical dependence.

It would be interesting to see more research done on this subject, as today’s classes of antidepressants are by no means one hundred percent effective. Unfortunately, due to marijuana’s tight scheduling in the United States, it is difficult for American researchers to conduct quality studies on its effects. Notably, the study mentioned above was done in Canada at McGill University and the University of Montreal, both in Quebec. In order for scientists to research marijuana in this country, they must obtain it from the National Institute on Drug Abuse (NIDA). Numerous scientists have criticized this supply as being less potent than the drug that is usually found on the street. Furthermore, an article in Scientific American points out that the government is reluctant to fund studies that propose to look for health benefits of marijuana. Instead federal funding is focused on studies of its detrimental effects, perhaps because the nation's drug policy is based on the assertion that marijuana has no medical use whatsoever. I think this policy is unwise because it might limit the development of potential new treatments for depression as well as other illnesses. When possible, the government should promote open scientific inquiry, not attempt to stifle it because the findings may contradict the reasoning for its policies.

Obesity and the Brain: Is There a Gene that Makes Us Fat?

A new study just published in the October issue of Behavioral Neuroscience suggests there may be a genetic component to why some people tend to eat more than others. The experiment tested 29 obese and 45 normal people for their genotype, motivation to eat, and energy consumption. The genotype that was studied has to do with the dopamine system in the brain, specifically the gene determining the amount of dopamine receptors. One of the two alleles for this gene, called the Taq1 A1 allele, “has been associated with a 30%–40% reduction in the density of the dopamine D2 receptor (DRD2).” About half the world's population carries the A1 allele. Most A1 carriers are heterozygous, meaning they carry one A1 allele and one A2 allele. The other half is homozygous for the A2 allele, meaning they have a higher number of dopamine receptors. So what does dopamine (the molecule shown on the left) have to do with eating? According to the study, “The reinforcing value of food is related to activity of the dopaminergic system. Food consumption increases brain dopamine levels in animals and humans.” It should be noted that the “reinforcing value of food” is measured by how hard someone will work to get food not how much pleasure one derives from eating food.

The study involved two behavioral experiments. In the first, the participants were given various foods and told to rate them in order of taste and personal preference. However, the rating was designed to mask the real purpose of the task, which was to see how much the subjects ate when food was freely available. The second experiment had the subjects press buttons on two different computers. Pressing buttons on one computer earned them points to eat a favorite food, whereas pressing buttons on the other earned them points to read a newspaper. This task measured how hard the participants were willing to work to get food. Based on these data, the researchers were able to divide the subjects into two groups, one low and one high on “food reinforcement.” The latter group, the ones who were willing to work hardest to earn food, consumed the most calories. In addition, the high reinforcers that were carriers of the A1 allele consumed even more calories. Yet some people with the A1 allele were also low in food reinforcement, and there was no difference among the two genotypes in that group. Instead, the A1 allele combined with high levels of food reinforcement was what made people in this group consume the most. The researchers speculated that this powerful combination could be a major risk factor for obesity.

The reason the A1 allele and its corresponding reduction in the number of dopamine receptors may increase the reinforcing value of food is similar to the way drugs act on our brains. Indeed, the study mentioned that, “Food is a powerful reinforcer that can be as reinforcing as drugs of abuse.” When dopamine receptors are stimulated (picture on the right), they produce a feeling of reward for whatever actions were taken to stimulate them. Both drugs and food can increase levels of dopamine and thus increase the feeling of reward. Having more dopamine receptors makes it easier to experience the reward, and thus less of the rewarding substance is needed to get the feeling. In contrast, to those with fewer receptors, more of the rewarding substance is needed to get the same feeling, and in some people, that substance may be food. There are many drugs that act on the dopamine system, including drugs for Parkinson’s disease and schizophrenia as well as illegal drugs like cocaine. This study leaves open the possibility that a future treatment for obesity and overeating may come from drugs that affect the dopaminergic system, especially for those individuals that have a genetic propensity for higher food reinforcement.

Depression: Two Treatments are Better than One

A new study published in the October 2007 issue of the Archives of General Psychiatry has found that a combination of cognitive behavioral therapy and anti-depressant medication is the best treatment option for teens with major depressive disorder. The Treatment for Adolescents with Depression Study followed a diverse group of 654 teens for 36 weeks. One group took the anti-depressant fluoxetine (brand name Prozac), another group engaged in cognitive behavioral therapy with a therapist, and yet another group was given both treatments. After 18 weeks, 69 percent of the teenagers taking fluoxetine alone and 65 percent of those participating in cognitive behavioral therapy alone showed improvement. In contrast, 85 percent of those receiving both treatments showed improvement after the 18 weeks. After 36 weeks, the difference in outcome for the three treatments diminished somewhat, with 86 percent of those in the combination therapy showing improvement compared to 81 percent of those in the other single-treatment groups.

Another significant finding of the study was that combining cognitive behavioral therapy with the anti-depressant also significantly reduced the rate of suicidal thinking in the teens. Although anti-depressants have helped many people with depression, they have ironically also been blamed for increasing the rate of suicidal thoughts, especially in teens. Most SSRIs (selective serotonin reuptake inhibitors) like fluoxetine are now required to come with “black-box” labels warning of the effect, and it is for this reason many doctors are wary of prescribing this type medication to teens even though it has been shown to be effective in most people. This side-effect was seen in the study with 15 percent of the teens in the fluoxetine-only group reporting suicidal thoughts. However, only 8 percent of the teens in combination therapy reported suicidal thoughts, which was closer to the 6 percent of teens in the cognitive behavioral therapy alone. This suggested to the study’s authors that the cognitive behavioral therapy in some way mitigated the negative effects of the fluoxetine and that the two treatments complemented each other well.

One thing I am left wondering about this study is why it did not include a control group given no treatment or a placebo. It would have been interesting to see whether or not there was a large difference between teens given a placebo plus cognitive behavioral therapy differed much from the ones given the combination treatment described above. In addition, they could have given a “placebo” therapy in combination with the fluoxetine to see if it was the actual cognitive behavioral therapy that produced the changes or just the act of consistently talking with a trusted adult. Also, since many people naturally recover from depression over time, it would have been interesting to compare the results of the study with a group of teens given no treatment. However, I can see how the risk of the teens harming themselves if not treated would outweigh the benefit of including a no-treatment group.

The results of this study in some ways seem to me like common sense. Of course two treatments should be better than one. Hopefully though, it will help end the practice of psychiatrists just giving teens an anti-depressant prescription and nothing else. Although anti-depressants have greatly advanced the treatment of the physical aspects of depression, in my view they may have also made traditional methods of therapy seem less important. However, this study not only proves that cognitive behavioral therapy is basically just as effective as anti-depressants, but that the choice does not have to be between one and the other. Maybe some day in the future there will be a single miracle pill that will cure all depression, but until then it does not serve patients well to forget about lower tech methods of treatment because of new exciting drugs.